2. Drug development consideration Toxicity: “All substances are poisons; there is none that is not a poison. The right dose differentiates a poison and a remedy” (Paracelsus, 1538) Drug absorption Injection: intravenous, intramuscular, subcutaneous Inhalation: aerosol (i.e., drugs for the treatment of emphysema, asthma, chronic obstructive pulmonary disease (COPD)) Insufflation: snorted (i.e.,, psychoactive drugs) Oral: needs to pass through the stomach Sublingual (i.e., cardiovascular, steroids, barbiturates) Transdermal (i.e., lidocaine, estrogen, nicotine, nitroglycerin) Rectal (i.e., suppository against fever)

3. Drug development consideration (cont.) Drug distribution Blood-brain barrier (BBB) Only small molecules pass i.e., water, oxygen, carbon dioxide Lipophilic compounds permeate as well, but not polar or ionic compounds (log K OW is important here) Drug redistribution and storage Body fat Drug metabolism and excretion Phase I: biotransformation in the liver Phase II: conjugation (glucuronic acid)

4. Salicylic acid It was known to reduce fever (Hippocrates, 5 th century BC) It was isolated from the bark of willow trees Problem: It causes nausea and vomiting Aspirin Chemical Name: acetylsalicylic acid It was first obtained by Gerhardt in 1853 The Bayer AG started to promote it as replacement for salicylic acid in 1899 It is a pro-drug for salicylic acid and generally has less side-effects (gastrointestinal bleeding, hives, etc.)

5. How does aspirin work? It transfers an acetyl group to a serine group and suppresses the prostaglandin synthesis

6. It is used as treatment for dull, consistent pain It acts by elevating the pain threshold by decreasing pain awareness Side effects Depression of respiratory center Constipation (used in the treatment of diarrhea) Excitation Euphoria (used in the treatment of terminally ill patients) Nausea Pupil constriction Tolerance and dependence (leads to withdrawal symptoms)

7. The methylation of the phenol function leads to the formation of codeine (morphine: log K ow =0.89, codeine: log K ow =1.19) The analgesic activity of codeine is only 0.1 % of morphine. But because codeine is converted to morphine by the liver (the OCH 3 group has to be replaced by the phenol group) it becomes 20 % as strong as the latter overall Thus, the free phenol groups seems to be very important Codeine is considered a pro-drug of morphine The greatly reduced initial activity is a result of the stable ether function

8. The modification of the alcohol function in morphine leads to enhanced analgesic activity (4-5 times) In particularly the acetyl compound (R=CH 3 CO) has shown to be much more effective (log K ow =1.55) It is less polar than morphine because of the loss of one OH group Thus, it can cross lipophilic blood-brain barrier (BBB) better which means that is has a faster onset

9. The acetylation of both OH groups in morphine affords the diacylation product (Heroin, Bayer AG, (1898-1910)) Its analgesic activity compared to morphine only about doubles It is significantly less polar than morphine (log K OW =2.36) because it does not possess a free phenol group, but the ester function rapidly hydrolyzed in the brain Heroin was used as cough suppressant and as non-addictive morphine substitute until it was found that it is habit forming as well

10. If the NMe group is replaced by a NH function, the analgesic activity will decrease to 25 %, most likely due to the increased polarity of the compound (additional hydrogen bonding) If the nitrogen atom is missing from the structure, the compound displays no activity at all  The aromatic ring is important as well because without it the compound is inactive as well The ether bridge does not seem to be important An extension of the NMe group i.e., NCH 2 CH 2 Ph group affords a compound that is 14 times more active than morphine itself An allyl group on the nitrogen (i.e., nalorphine) makes a compound an antagonists which counters morphine’s effect

11. Important parts of the molecule Hydrogen bond Certain R-groups for van der Waals interactions Ionic interaction Chirality center Unimportant parts Ether bridge Double bond

12. Ultimately, the structure can be reduced to a pharmacophore, which is the “active part” of a drug involved in the molecular recognition However, not everything that contains the pharmacophore is active as well Levorphanol (5x)Bremazocine (200x)Zero activity!Etorphine (1000-3000x)

13. Fentanyl It possesses most of the key parts of the morphine family (only missing the OH-group on the benzene ring) About 100 times more potent compared to morphine Mainly used for anesthesia in operating rooms 3-Methylfentanyl About 400-6000 times more potent compared to morphine (cis isomers are more potent than the trans isomers) Used as chemical weapon (i.e., 2002 Moscow Theatre Hostage Crisis in which 130 hostages died in a gas attack)

14. Procaine First synthesized in 1905 (A. Einhorn) Trade name: Novocain(e) Good local anesthetic, used in dentistry Short lasting due to the hydrolysis of the ester function (half-life: 40-84 s, log K ow =2.14, pK a =8.05) Lidocaine Ester function replaced by amide function, which is chemically more robust Two ortho-methyl group protect the amide from enzymatic degradation (half-life: 1.5-2 hours, log K ow =2.44, pK a =7.90)

15. Mepivacaine: local anesthetic, faster onset than procaine, (log K ow =1.95, pK a =7.70) Ropivacaine: local anesthetic, half-life: 1.5-6 hours, (log K ow =2.90, pK a =8.07) Trimecaine: local anesthetic, half-life: 1.5 hours, (log K ow =2.41, pK a = ~8) Prilocaine: local anesthetic (dentistry), half-life: 10-150 minutes, (log K ow =2.11, pK a =8.82)